3 Many important needs in Oncology…We need to know how we got here…We need to determine how to move forward…

4 WE ARE LIVING A TRUE THERAPEUTIC REVOLUTION IN CANCER CAREThe cancer revolution is a result of long investment in research to understand cancer’s biology, together with advances in the way care is delivered to patients every day.Today’s patients benefit from a range of important advances, such as a growing number of approved cancer drugs, more precise and effective surgical techniques, and comprehensive supportive care measures.American Society of Clinical Oncology.J Oncol Pract Mar 1;10(2):

5 The State of Cancer Care in America 2014NEW SCIENTIFIC, TECHNICAL AND ECONOMIC TRENDS ARE LIKELY TO ALTER ONCOLOGY CARE DELIVERY MORE SIGNIFICANTLY IN THE NEXT 20 YEARS THAN IN THE LAST 50.Progress in 5-year survivalAs a result of this progress, more people are survivingcancer than ever before

12 PATIENTS CHARACTERISTICS: PROFILE 1001n (N=149)%Median Age52.0(21–86)Men/Women73/7649/51Ethnic White Asian OttherSmoking status NeverFormerPresent71 28 <1Histology Adenocarcinoma Large-cell carcinoma Squamous-cell carcinoma Other97 <1 1 1ECOG: ≥2Number of previous advanced metastatic treatment regimens ≥4Camidge DR et al. Lancet Oncol (10):1011-9We always gave data on 119 patients which was cohort presented by Camidge at ASCO 2011During one of the poster discussions some emphasis was put on the wide age range, which here is 21 to 86,Don’t remember that we do not only have never smokers. Approx one third is former smoker and this will also be emphasized in 1005Esst adenocarcinoma, but in a poster from East Asia fe on 392 tissue samples using RT-PCR and validation with sequencing, they found overall 6.1% ALK pos but this in 5 pts with squamous cell CA and 5 pts with adenosquamous CA. (14 were pure adeno)Updated info shows now 24 pts in first line, which is more than the 13 pts reported by Camidge at ASCO last yearHowever, till approx one third has 3 or more previous treatment linesECOG; Estado funcional del Eastern Cooperative Oncology Group performance status.

31 Is there a role for a 3rd line ALK inhibitor? • Resistance mechanismHow should we integrate genetic and clinical information?1L2L3LIs there a role for a 3rd line ALK inhibitor?• CNS disease• Resistance mechanismCrizotinibCeritinib, alectinib etcor platinum/pem1L2LWhich ALK inhibitor?• CNS efficacy• Tolerability• ResistancemechanismNovel ALK inhShaw A. ESMO 2014

37 Beyong first line… SOME KEY QUESTIONSWhy did 26% of the patients who received crizotinib in PROFILE 1014 not have a response?Are there combinations of agents that might convert good partial responses to durable complete responses?Is crizotinib still active after PD?Brain mets management

38 Mechanisms of therapeutic resistance to kinase inhibitors.Mechanisms of therapeutic resistance to kinase inhibitors. Resistance to targeted therapies can be classified as primary resistance or acquired resistance. Primary resistance is defined as a de novo lack of treatment response and can be mediated by tumor intrinsic factors, such as concurrent genetic alterations within the drug target or within other signaling molecules, and by patient-specific factors, such as drug–drug interactions. Conversely, acquired resistance refers to disease progression after an initial response to the targeted therapy. Acquired resistance develops while the patient is still receiving the targeted therapy, implying that the tumor has developed an “escape” mechanism to evade continuous blockade of the target. These “escape” mechanisms include target modification (gene amplification, second-site mutations, splice variants), the emergence of bypass signaling tracks, histologic transformation, as well as other less well-characterized mechanisms such as increased growth factor production. Examples of strategies to overcome acquired resistance, which are discussed in more detail within the text, include alternative doses or schedules of the targeted inhibitor, development of more potent “next-generation” inhibitors, dual blockade of the initial target with two or more target-specific agents, and combination drug strategies designed to suppress compensatory signaling loops.Lovly C M , and Shaw A T Clin Cancer Res 2014